Vaccination strategies for Parkinson disease

Abstract

Parkinson disease is the second most common neurodegenerative disease in the world, but there is currently no available cure for it. Current treatments only alleviate some of the symptoms for a few years, but they become ineffective in the long run and do not stop the disease. Therefore it is of outmost importance to develop therapeutic strategies that can prevent, stop, or cure Parkinson disease. A very promising target for these therapies is the peripheral immune system due to its probable involvement in the disease and its potential as a tool to modulate neuroinflammation. But for such strategies to be successful, we need to understand the particular state of the peripheral immune system during Parkinson disease in order to avoid its weaknesses. In this review we examine the available data regarding how dopamine regulates the peripheral immune system and how this regulation is affected in Parkinson disease; the specific cytokine profiles observed during disease progression and the alterations documented to date in patients' peripheral blood mononuclear cells. We also review the different strategies used in Parkinson disease animal models to modulate the adaptive immune response to salvage dopaminergic neurons from cell death. After analyzing the evidence, we hypothesize the need to prime the immune system to restore natural tolerance against α-synuclein in Parkinson disease, including at the same time B and T cells, so that T cells can reprogram microglia activation to a beneficial pattern and B cell/IgG can help neurons cope with the pathological forms of α-synuclein.

Microglia Response During Parkinson’s Disease: Alpha-Synuclein Intervention

“…We have shown that allelic variance of Mhc2ta related to lower expression MHCII levels resulted in increased a-syn toxicity in rats that correlated with a higher microglia response ( Jimenez-Ferrer et al, 2017 ), thus suggesting that a failure in the adaptive immune signal (MHCII-CD4 T cell) will have consequences in the neuronal survival to a-syn insult. In PD patients the CD4 population seems to be altered ( Fiszer et al, 1994 ; Saunders et al, 2012 ; Stevens et al, 2012 ) and they seem to be more prone to apoptosis, and differ in their activation state, which could suggest that a failure of the CD4 cells response might be happening in PD ( Romero-Ramos et al, 2014 ). However, we should also consider a differential response of the T-cells to the different types of a-syn presented through the disease, thus changing the nature of their response as disease progress.…”

Immunotherapy in Parkinson’s Disease: Micromanaging Alpha-Synuclein Aggregation

“…Targeting the immune system and using immunotherapy are promising strategies for treating PD [ 86 ]. Immunotherapy holds the key to be the one of the disease-modifying strategies against PD, as immunizing patients in their early stages and prior to the accumulation of α-syn deposits would be the most effective strategy in preventing the progression of the disease [ 28 ].…”

“…As α-syn aggregates are the target of immunotherapy trials in PD, an important consideration and possible side effect is the induction of inflammatory autoimmunity mediated by Th17 cells (subset of T helper cells) as α-syn is an endogenous self-protein and Th17 cells have been shown to be involved in the neurodegenerative neuroinflammatory process [ 86, 88 ]. No study using antibodies to induce protection in PD models have studied the T cell response [ 86 ]. Therefore for immunotherapy against α-syn to be an effective treatment, it must consider the adaptive immune response to regulate the response against α-syn and immunotherapy must be initiated prior to the formation of α-syn aggregates.…”

New Generation Peptide-Based Vaccine Prototype

“…MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin drug of MPP+, which causes permanent symptoms of PD by destroying dopaminergic neurons in the substantia nigra of the brain for mouse modeling [65]. PD01A is a Phase 1 epitope vaccine in experimental -a synthetic a-syn mimicking peptide-polymer based on a-syn aggregate by inducing an immune response that generates antibodies specifically against it [66]. In general, vaccines are developed according to the T cell response, but a peptide epitope with a three-celled peptide epitope with a three-cell universal peptide such as Syn85-99 (AGSIAAATGFVKKDD), α-Syn109-126 (QEGILEDMPVDPDNEAYE), α-Syn126-140 (EMPSEEGYQDYEPEA) and P30 (FNNFTVSFWLRVPKVSASHLE) epitope vaccines comprising three peptide-based epitope vaccines comprising different α-Syn peptides, but consisting of different B cell epitopes as follows, are noted for their high immunogenicity [67].…”